Platelet-activating factor receptor activation promotes prostate cancer cell growth, invasion and metastasis via ERK1/2 pathway

  • Authors:
    • Wenbin Ji
    • Jin Chen
    • Yucheng Mi
    • Guanliang Wang
    • Xinjian Xu
    • Weizhen Wang
  • View Affiliations

  • Published online on: May 12, 2016     https://doi.org/10.3892/ijo.2016.3519
  • Pages: 181-188
Metrics: HTML 0 views | PDF 0 views     Cited By (CrossRef): 0 citations

Abstract

Platelet-activating factor (PAF) and its receptor (PAFR), have been reported to participate in many cellular processes of cancer. However, little is known about their function in prostate cancer. In the present study, we found that PAFR was overexpressed in prostate cancer cells. PAF stimulation dose-dependently promoted the invasion, migration and growth of prostate cancer cells in vitro, while knockdown of PAFR inhibited the effect of PAF on prostate cancer cells. We further found that PAFR promoted prostate cancer cell growth and metastasis in vivo. Moreover, we found that PAFR activation increased MMP-3 expression and decreased E-cadherin expression of prostate cancer cells in vitro and in vivo. Finally, we found that PAFR time-dependently induced activation of ERK1/2, and ERK1/2 pathway contributed to PAFR-mediated prostate cancer cell invasion, migration and growth. Together, our findings demonstrate that PAFR can activate ERK1/2 pathway, and subsequently increase MMP-3 expression and decrease E-cadherin expression, which finally promote prostate cancer cell growth, invasion and metastasis. Thus, PAFR may act as a potential target for therapeutic use of prostate cancer.

Introduction

Prostate cancer is one of the most common types of cancer worldwide, and acts as a leading cause of cancer-related death in men (1). While early prostate cancer can be cured, patients with advanced prostate cancer often suffered from invasion and metastasis, which leads to death of prostate cancer patients (2). Therefore, discovering novel molecular biomarkers associated with prostate cancer progression, especially those regulating the invasion and metastasis, may provide potential molecular targets for the detection and therapy of prostate cancer.

PAF is known as a phospholipid mediator of inflammation, and further studies proved that PAF plays a pivotal role in many diseases, including cancer (3,4). It is reported that PAF promotes the migration and proliferation of breast cancer cells (5), and contributes to the invasiveness and motility of melanoma cells (6). PAF exerts its biological effects mainly via activating PAFR. As a member of G-protein coupled receptor (GPCR) family, PAFR has been found to promote the malignant development of esophageal squamous cell carcinoma via PI3K/AKT pathway (7), and enhance the growth of ovarian cancer cells through cooperating with EGFR (8). However, it is reported that elevated PAFR expression is significantly associated with smaller tumor size, absence of lymph node and organ metastasis and low tumor histopathological stage in gastric adenocarcinoma (9). In prostate cancer, the function of PAFR remains elusive.

Given that PAFR may act as contrasting effect on the progression of different cancers, the present study aimed to investigate the effect of PAF and PAFR interaction in the progression of prostate cancer cells. We unexpectedly found that activation of PAFR by PAF stimulated the growth, invasion and metastasis of prostate cancer cells via the ERK1/2 pathway.

Materials and methods

Cell lines and reagents

All cell lines were purchased from the American Type Culture Collection (ATCC; Manassas, VA, USA). Human prostate cancer cell lines LNCap, PC-3, PC-3M and DU-145 were maintained in RPIM-1640 medium containing 10% fetal bovine serum (FBS) in 5% CO2 atmosphere at 37°C. Normal prostate cell line RPWE-1 was maintained in K-SFM medium containing 10% FBS in 5% CO2 atmosphere at 37°C. ERK1/2 special inhibitor U0126, PAF and DMSO were purchased from Sigma-Aldrich (St. Louis, MO, USA). Antibodies against PAFR, E-cadherin, ERK1/2 and β-actin were obtained from Santa Cruz Biotechnology (Santa Cruz, CA, USA). Antibody against phosho-ERK1/2 was obtained from Cell Signaling Technology (Danvers, MA, USA).

Cell transfection

A specific siRNA targeting PAFR (siPAFR) was purchased from GenePharma Co., Ltd., (Shanghai, China) with the sequence of 5′-CUGGGCGUCAUCACUUAUA-3′ to transiently silence PAFR expression. A scramble siRNA was used as control siRNA (siCtrl). Cells were incubated with siPAFR or siCtrl for 36 h using the Lipofectamine 2000 trans-fection reagent (Invitrogen), according to the manufacturer's instruction. Knockdown efficiency was determined by western blotting, and the cells were subjected to the experiments described below.

Furthermore, to stably silence PAFR expression in DU-145 cells, a PAFR shRNA (shPAFR) was obtained from GenePharma, while a scrambled shRNA was used as control shRNA (shcontrol). Cells were incubated with shPAFR or shControl for 36 h using the Lipofectamine 2000 transfection reagent (Invitrogen), and the stable clones were selected by G418. Knockdown efficiency was detected by western blotting.

Western blotting

Total proteins from cell lines or transplanted tumor tissues of mice were isolated using RIPA buffer with protease inhibitor and phosphatase inhibitor. The concentration of protein was determined by BCA assay (Applygen Technologies, Inc., Beijing, Beijing, China). Then, equal amounts of protein were separated in 10% polyacrylamide gel and electrotransferred on PVDF membrane (Millipore Corp., Billerica, MA, USA). The membrane was probed with primary antibodies overnight, and then incubated with secondary antibodies for 1 h. Next, the membrane was visualized by enhanced chemiluminescence kit (Applygen Technologies). The density of each band was analyzed with Quantity One software.

In vitro invasion assay and migration assay

In vitro invasion assay and migration assay were performed using Transwell chambers (Corning Costar, Corning, NY, USA). Briefly, cells at the density of 1×106 cells/ml were plated in serum-free medium on upper chambers coated with Matrigel in invasion assay, whereas 600 μl of 1640 medium supplemented with 20% FBS was added into the lower chambers. Sixteen hours later, cells passed through the membrane were stained with crystal violet, and the numbers of cells were counted under a light microscope in seven random fields. For in vitro migration assay, cells at the density of 1×106 cells/ml were plated in serum-free medium on upper chambers without Matrigel, and cells were allowed to migrate for 16 h. The migrated cells were stained with crystal violet, and the numbers of cells were counted under a light microscope in seven random fields.

Real-time PCR

Total RNA was isolated from cells using TRIzol reagent (Invitrogen), following the manufacturer's instruction. Then, reverse transcription PCR was carried out using Omniscript RT-PCR kit (Qiagen, Hilden, Germany). Next, real-time PCR was performed using the primers of E-cadherin (forward, 5′-CGAGAGCTACACGTTCACGG-3′ and reverse, 5′-GGGTGTCGAGGGAAAAATAGG-3′; MMP-3 (forward, 5′-CTGGACTCCGACACTCTGGA-3′ and reverse, 5′-CAGGAAAGGTTCTGAAGTGACC-3′); or β-actin (forward, 5′-CATGTACGTTGCTATCCAGGC-3′ and reverse, 5′-CTCCTTAATGTCACGCACGA-3′) under the following conditions: 10 min at 94°C, followed by 40 cycles of 15 sec at 95°C and 1 min at 60°C. β-actin served as an internal control. The relative mRNA expression of MMP-3 and E-cadherin was determined by the 2−ΔΔCt method.

ELISA assay

After stimulation with or without PAF, the supernatants of DU-145 cells was collected and subjected to MMP-3 ELISA assay (Invitrogen), according to the manufacturer's instruction. To detect MMP-3 level in transplanted tumor tissues of mice, total proteins from transplanted tumor tissues of mice were isolated in RIPA buffer with protease inhibitor, and then MMP-3 ELISA kit (Invitrogen) was used to determine MMP-3 protein expression.

In vitro CCK-8 proliferation assay

Cell proliferation was determined by CCK-8 assay kit (Jingmei Biotech Co., Ltd., Shanghai, China). Briefly, cells were seeded at 800 cell/well in a 96-well plate, and incubated for 6 h. Then, cells were stimulated with or without PAF for 72 h. Next, 15 μl of CCK-8 was added into the plate and cells were further incubated for 2 h. Finally, optical density (OD) was observed using a microplate reader (Bio-Rad Laboratories) at 490 nm.

In vivo proliferation and metastasis assay

Male BABL/c nude mice at four weeks old were purchased and maintained in the pathogen-free conditions under the approval of the Animal Care and Use Committee of Wenzhou Medical University. Sixteen mice were randomly divided into two groups (n=8 each group). Then shControl cells or shPAFR cells (2×105 cells) were subcutaneously injected at the back of the mice. Tumors were formed in one week. The length and width of tumors in mice were measured every week, and tumor volumes were estimated with the formula of 0.52 × length × width2. Seven weeks later, the mice were sacrificed. Tumor tissues were lysed in RIPA buffer to further detect MMP-3 and E-cadherin expression. The livers were fixed in 4% paraformaldehyde, sectioned into slices and stained with H&E. Then the number of micrometastasis in liver was counted under a microscope.

Statistical analysis

Experiments were performed three times, and data are presented as mean ± standard deviation (SD). Statistical analysis was performed using SPSS version 17.0 software (SPSS, Inc., Chicago, IL, USA). The statistical significant difference was determined by the Student's t-test between two groups, or by non-parametric ANOVA among multiple groups. P<0.05 was considered to be statistically significant.

Results

Overexpression of PAFR in prostate cancer cells

In the present study we detected the protein level of PAFR in human normal prostate RPWE-1 cells and prostate cancer LNCap, PC-3, PC-3M and DU-145 cells by using western blotting. The results showed that the PAFR expression level was significantly higher in prostate cancer cells as compared to RPWE-1 cells (Fig. 1).

PAFR activation induces invasion and migration of prostate cancer cells in vitro

To investigate the role of PAFR in prostate cancer cells, DU-145 cells were selected and PAF was used to activate PAFR. In vitro invasion and migration assays were performed to determine the invasive and migration effect of PAFR activation on prostate cancer cells. We found that cell invasion was dose-dependently increased after incubation with different concentration of PAF (Fig. 2A). In vitro migration assay showed that PAF dose-dependently induced the migration of DU-145 cells (Fig. 2B). These findings indicate that PAFR activation is involved in prostate cancer cell invasion and migration in vitro.

PAFR activation regulates the expressions of MMP-3 and E-cadherin in vitro

After incubation of PAF with a concentration of 10, 50 and 100 nM, respectively, the mRNA and protein levels of MMP-3 were observed by real-time PCR and ELISA assay, respectively. The results showed that the production of MMP-3 was increased after PAF stimulation, in a dose-dependent manner (Fig. 3A and C). We further found that PAF stimulation decreased the expression of E-cadherin at mRNA and protein levels (Fig. 3B and D). These findings suggest that PAFR activation can regulate the levels of MMP-3 and E-cadherin in prostate cancer cells.

Knockdown of PAFR inhibits prostate cancer cell invasion and migration in vitro

To confirm the effect of PAFR on prostate cancer cells, DU-145 cells were transfected with siPAFR to reduce PAFR expression. Using western blotting, we found that siPAFR significantly reduced PAFR expression by >70% compared with the siCtrl transfection (Fig. 4A). Using in vitro invasion assay and migration assay, we found that PAF stimulation promoted the invasion and migration in siCtrl cells, whereas knockdown of PAFR attenuated the invasion and migration of DU-145 cells induced by PAF (Fig. 4B and C). Furthermore, after knockdown of PAFR, PAF-mediated increase of MMP-3 expression, as well as decrease of E-cadherin was suppressed (Fig. 4D and E). These data confirm that PAFR contributes to prostate cancer cell invasion and migration.

PAFR activation induces activation of ERK1/2 in vitro

Next, we found that PAF stimulation induced activation of ERK1/2 in DU-145 cells, in a time-dependent manner, and peak activation was observed at 30 min (Fig. 5A). However, knockdown of PAFR inhibited PAF-induced activation of ERK1/2 (Fig. 5B). These findings suggest that PAF can mediate ERK1/2 activity via PAFR.

ERK1/2 pathway is required for PAFR-mediated prostate cancer cell invasion and migration

To investigate the function of ERK1/2 pathway in PAFR-mediated prostate cancer cell invasion and migration, cells were incubated with U0126 for 1 h before PAF stimulation to inhibit ERK1/2 activation. In vitro invasion assay and migration assay showed that inhibition of ERK1/2 activation suppressed PAF-mediated cell invasion and migration (Fig. 6A and B). Moreover, inhibition of ERK1/2 activation inhibited PAF-mediated increase of MMP-3 expression and decrease of E-cadherin expression (Fig. 6C and D). Together, these data suggest that ERK1/2 pathway is essential for PAFR-mediated prostate cancer cell invasion and migration.

PAFR activation promotes the metastasis of prostate cancer cells in vivo

To detect the effect of PAFR on the metastasis of prostate cancer cells in vivo, cells were transfected with pcDNA3.1-shPAFR to stably decrease PAFR expression (Fig. 7A). Then, the mice were injected subcutaneously with shControl and shPAFR cells into the back, respectively. Eight weeks later, the mice were sacrificed, and liver micrometastasis was observed under a microscope. The results showed that knockdown of PAFR greatly decreased the number of micrometastasis in the liver (Fig. 7B). We found that after knockdown of PAFR, E-cadherin expression was increased while MMP-3 expression was decreased in tumor tissues (Fig. 7C and D). These results suggest that PAFR participates in the metastasis of prostate cancer cells in vivo.

Effect of PAFR on prostate cancer cell proliferation in vitro and in vivo

We examined the effect of PAFR on cell proliferation of prostate cancer cells. In vitro CCK-8 proliferation assay showed that PAF stimulation dose-dependently promoted the proliferation of DU-145 cells in vitro, whereas knockdown of PAFR suppressed the effect of PAF on cell proliferation (Fig. 8A and B). Similarly, in vivo growth assay showed that knockdown of PAFR inhibited the proliferation of DU-145 cells in mice (Fig. 8C). These results suggest that PAFR is involved in prostate cancer cell proliferation. Moreover, inhibition of ERK1/2 pathway attenuated PAF-mediated cell growth of DU-145 cells in vitro (Fig. 8D), indicating PAFR regulated prostate cancer cell growth via the ERK1/2 pathway.

Discussion

In the present study, we found that PAFR induced activation of the ERK1/2 pathway, leading to the upregulation of MMP-3 and downregulation of E-cadherin expression, ultimately inducing the invasion and metastasis of prostate cancer cells in vitro and in vivo. We also found that PAFR contributed to prostate cancer cell proliferation via ERK1/2 pathway. These findings suggest that PAFR may be an essential mediator in prostate cancer progression.

PAF plays an important role in many cellular processes. It is reported that PAF can induce activation of matrix metallo-proteinase-2 activity and vascular endothelial cell invasion and migration (10). In cancer, Melnikova et al (11) have reported that PAF contributs to the metastasis of melanoma. PAF binds the PAFR, which belongs to GPCR family and is involved in the tumorigenesis and progression of many cancers. It is reported that PAFR is essential for the malignant potential in BRCA1 dysfunctional at-risk ovarian epithelium (12), and PAFR activation promotes the growth of ovarian cancer cells (13). In addition, studies have found that crosstalk between protease-activated receptor 1 and PAFR regulates melanoma metastasis (14) and PAFR activation augments the growth and metastasis of lung cancer (15). However, some studies have found that lower expression of PAFR correlats with poor differentiation and a poor prognosis in patients with hepatocellular carcinoma after hepatectomy (16), and PAFR expression is negative associated with histopathological stage and grade and patient survival in gastric adenocarcinoma (9). In prostate cancer cells, Jan and Chao (17) found that a specific PAFR antagonist inhibits prostate cancer cell growth, but the function of PAFR in the progression of prostate cancer cells and the underlying molecular mechanisms are still not very clear. In the present study, we found that PAFR expression was upregulated in prostate cancer cells. Activation of PAFR by PAF dose-dependently stimulated the growth, invasion and migration of prostate cancer cells in vitro. Knockdown of PAFR inhibited PAF-mediated cell growth, invasion and migration. Furthermore, knockdown of PAFR suppressed the growth and metastasis of prostate cancer cells in vivo. These data suggest that PAFR may act as a vital mediator in prostate cancer cells.

We further found that PAFR activation decreased E-cadherin expression and increased MMP-3 expression of prostate cancer cells in vitro, whereas knockdown of PAFR attenuated the effect of PAF on E-cadherin and MMP-3 expression. Moreover, knockdown of PAFR increased E-cadherin expression and decreased MMP-3 expression of prostate cancer cells in vivo. MMP-3 is an important member of the matrix metalloproteinase family, which is required for the dissolution of stromal collagen during tumor dissemination (18). It is considered that MMP-3 is involved in the invasion and metastasis of many cancers including prostate cancer (1921). E-cadherin is a cell-cell adhesion protein and a well-documented tumor suppressor (22). Many studies have proved that downregulation of E-cadherin participates in the occurrence and development of prostate cancer (23,24). In the present study, we showed that PAFR induced prostate cancer cell invasion and metastasis in vitro and in vivo, and decreased E-cadherin expression and increased MMP-3 expression, suggesting that PAFR may induce the invasion and metastasis of prostate cancer cells via regulation of MMP-3 and E-cadherin expression.

The MAPK ERK1/2 pathway is involved in a wide variety of cellular processes in cancer development (25,26). Studies have shown that ERK1/2 activation participates in cell growth, invasion, malignant transformation and drug resistance of prostate cancer (27,28). The ERK1/2 pathway can be activated by many growth factors and cytokines that are important in the progression of cancer. In the present study, we found that PAF induced activation of ERK1/2 via PAFR. Moreover, using an ERK1/2 specific inhibitor, we found that ERK1/2 pathway was required for PAFR-mediated cell growth, invasion and metastasis of prostate cancer cells.

In conclusion, our data demonstrate that PAFR is over-expressed in prostate cancer cells. PAFR promotes prostate cancer cell invasion and metastasis of prostate cancer cells in vitro and in vivo, possibly via activation of ERK1/2 pathway and regulation of E-cadherin and MMP-3 expression. We also showed that PAFR stimulates the growth of prostate cancer cells via ERK1/2 pathway. The present study provides evidence showing that PAFR may have a potential value in early detection and therapy for prostate cancer.

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July 2016
Volume 49 Issue 1

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APA
Ji, W., Chen, J., Mi, Y., Wang, G., Xu, X., & Wang, W. (2016). Platelet-activating factor receptor activation promotes prostate cancer cell growth, invasion and metastasis via ERK1/2 pathway. International Journal of Oncology, 49, 181-188. https://doi.org/10.3892/ijo.2016.3519
MLA
Ji, W., Chen, J., Mi, Y., Wang, G., Xu, X., Wang, W."Platelet-activating factor receptor activation promotes prostate cancer cell growth, invasion and metastasis via ERK1/2 pathway". International Journal of Oncology 49.1 (2016): 181-188.
Chicago
Ji, W., Chen, J., Mi, Y., Wang, G., Xu, X., Wang, W."Platelet-activating factor receptor activation promotes prostate cancer cell growth, invasion and metastasis via ERK1/2 pathway". International Journal of Oncology 49, no. 1 (2016): 181-188. https://doi.org/10.3892/ijo.2016.3519